As is well-known, peptides having a common structure (Phe-X-Gly-Leu-Met-NH2: SEQ ID NO:1) at a C terminus of their amino acid sequences are collectively referred to as tachykinin. Up to now, as tachykinin in mammals, three types, i.e., substance P (amino acid sequence: H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2: SEQ ID NO:2), neurokinin A (amino acid sequence: H-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2: SEQ ID NO:3) and neurokinin B (amino acid sequence: H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2: SEQ ID NO:4) have been identified. These three tachykinins are neuropeptides commonly distributed in living organisms. Among these three tachykinins, physiological functions in substance P have been studied in most detail.
Substance P is the neuropeptide present in the living organisms of mammals and composed of 11 amino acid residues. This substance P has been known to be involved in various pathological conditions such as asthma, inflammation, pain, psoriasis, migraine, dyskinesia, cystitis, schizophrenia, emesis and anxiety, due to its localizations and functions (Non-patent Document 1).
The NK1 receptor has been identified as a receptor which exhibits a high affinity with substance P in the living organisms. That is, it has been found that substance P acts as an agonist which causes intracellular signal transduction by interacting with the NK1 receptor. Furthermore, there are antagonists which can antagonize or block binding between substance P which is such an agonist and the NK1 receptor. It has been also known that disorders, symptoms and diseases which can be ameliorated by such antagonists are widely ranged.
Examples of those conditions and diseases may include: respiratory diseases (such as cough, asthma, airway hypersensivity), cutaneous diseases (such as contact dermatitis, atopic dermatitis, inflammation, flare, urticaria, eczema and psoriasis), nervous inflammatory diseases (such as arthritis, migraine, nociception), CNS diseases (such as depression, manic disease, schizophrenia, stress-related disorder, obsessive-compulsive disorder, phobia, anxiety, alcohol dependency, psychoactive agent abuse, Parkinson's disease, dyskinesia, psychosis), eating disorders (e.g., hyperphagia, bulimia, anorexia nervosa, eating behavior disorder), pains (such as postoperative pain, chronic pain, neuropathic pain), pruritus, emesis, gastrointestinal disorder, renal disorder, urinary disorder, eyeball inflammation, allergic rhinitis, sleep disorder, premenstrual syndrome, obesity, headache, bladder disorder, urogenital disorder.
Various NK1 antagonists have been developed for the purpose of treating or preventing the symptoms and the diseases mediated by the NK1 receptor. For example, Non-patent Document 2 shows clinical trial examples that the NK1 receptor antagonist is effective for various diseases such as anxiety, depression, psychosis, schizophrenia and emesis. Also, Non-patent Document 3 shows clinical trial examples that the NK1 receptor antagonist is effective as an antiemetic drug.
Based on such findings, various NK1 receptor antagonists have been developed and reported. A majority of the reported NK1 receptor antagonists is a peptidic analog obtained by substituting a part of amino acid residues which compose substance P from the mammal with a D-amino acid residue(s) (see Non-patent Document 4 and Patent Document 1).
As mentioned above, the NK1 receptor antagonists developed until now are the peptides. No good pharmacodynamic nature is obtained from the peptide type NK1 receptor antagonist, which exerts only its limited activity in the living organisms. The peptide type NK1 receptor antagonist causes side effects due to its antigenicity to and agonistic action upon human bodies.
In response, it has been reported that a non-peptide type NK1 receptor antagonist is now under development (Non-patent Document 5, Patent Document 2).    Patent Document 1: U.S. Pat. No. 2,783,520    Patent Document 2: JP 2006-89499-A    Non-patent Document 1: Takayanagi, K., “Receptors on Cell Membrane” published by Nanzando, 1998    Non-patent Document 2: Kramer M S et al., Science 281 (5383), 1640-1645 (1998)    Non-patent Document 3: Gesztesi Z et al., Anesthesiology 93(4), 931-937 (2000)    Non-patent Document 4: Zubrzycka M et al., Endocrine Regulations, 34(1), 13-18 (2000)    Non-patent Document 5: Rost K et al., Med Monatsschr Pharm 29(6), 200-205 (2006)